SK17142002A3 - Thiazolidinedione salt for treatment of diabetes mellitus - Google Patents

Abstract

A novel pharmaceutical compound 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione hydrobromide or a solvate thereof, a process for preparing such a compound, a pharmaceutical composition comprising such a compound and the use of such a compound in medicine.

Description

Technical field

The invention relates to a novel medicament, to a process for its manufacture and to its use in medicine.

BACKGROUND OF THE INVENTION

European Patent Application Publication No. 0,306,228 relates to certain thiazolidinedione derivatives which are described as having hypoglycemic and hypolipidemic activity. The compound of Example 30 of EP 0 306 228 is 5- [4- [2 (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione (also referred to as Formula I compound) .

International Patent Application Publication No. WO 94/05659 discloses certain salts of the compounds of EP 0 306 228, such as salts formed with mineral acids such as hydrobromic, hydrochloric and sulfuric acids, and organic acids such as methanesulfonic acid, tartaric acid salts. , and in particular maleic acid.

SUMMARY OF THE INVENTION

It has now been found that the compound of formula I forms a novel hydrobromide salt (also referred to herein as Hydrobromide), which is particularly stable and thus suitable for large-scale preparation and processing. The hydrobromide also has a high melting point, is particularly well soluble in water and exhibits good flow properties in the unfilled state. Surprisingly, it can therefore be easily processed by the pharmaceutical;

on a large scale, especially grind; on a large scale.

This new salt can be prepared; in an efficient, economical and reproducible manner that is special; suitable for large-scale production.

The novel hydrobromide also exhibits useful pharmaceutical properties. In particular, it appears to be useful in the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

Accordingly, the present invention provides 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione hydrobromide, or a solvate thereof.

A suitable hydrobromide is monohydrobromide.

According to one preferred aspect, the hydrobromide exhibits the substantially infrared spectrum shown in FIG. First

According to one preferred aspect, the hydrobromide exhibits substantially the Raman spectrum shown in FIG. Second

According to one preferred aspect, the hydrobromide exhibits a substantially powder X-ray diffractogram (XRPD) shown in Table 1 or shown in FIG. Third

According to one preferred aspect, the hydrobromide essentially exhibits the solid-state ¹³ C NMR spectrum shown in FIG. 4th

The hydrobromide also preferably has a melting point in the range from 175 to 185 ° C, in particular from 180 to 185 ° C, for example a melting point of 181 ° C.

The hydrobromide also exhibits a T to ₃ tup in the range of 180-186 ° C, for example at 182.5 ° C.

Accordingly, the present invention is preferably a Hydrobromide having two or more of the following features:

(i) the infrared spectrum substantially shown in FIG. i;

(ii) The Raman spectrum substantially shown in FIG. 2;

(iii) an X-ray powder diffraction pattern substantially as set forth in Table 1 or shown in FIG. 3;

(iv) a solid-state ¹³ C NMR spectrum substantially depicted in FIG. 4; and (v) a melting point in the range of 175 to 185 ° C, in particular in the range of 180 to 185 ° C, for example a melting point of 181 ° C.

The present invention includes the Hydrobromide or solvate thereof isolated in pure form or in admixture with other substances. Thus, in one aspect, the present invention provides the Hydrobromide or solvate thereof in isolated form.

Accordingly, in a further aspect, the present invention provides the Hydrobromide or solvate thereof in purified form.

In yet another aspect, the present invention provides the hydrobromide or solvate thereof in crystalline form.

The present invention further provides the Hydrobromide or solvate thereof in a solid pharmaceutically acceptable form, such as a solid dosage form, especially when adapted for oral administration.

The present invention further provides the Hydrobromide or solvate thereof in a pharmaceutically acceptable form, in particular in bulk form, in particular in a form that can be comminuted.

The present invention also provides the Hydrobromide or solvate thereof in a pharmaceutically acceptable form, in particular in bulk form, such form having good flow properties, in particular flow properties in bulk form.

A suitable solvate is a hydrate.

The present invention also provides a process for the preparation of a Hydrobromide or solvate thereof, which comprises 5 - [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione ( the compound of formula (I) or a salt thereof, preferably dispersed or dissolved in a suitable solvent, is reacted with a source of hydrogen bromide, followed by the preparation of a Hydrobromide solvate if necessary; and the hydrobromide or solvate is isolated.

A suitable reaction solvent is an alkanol such as propan-2-ol, or a hydrocarbon such as toluene, a ketone such as acetone, an ester such as ethyl acetate, an ether such as tetrahydrofuran, a nitrile such as acetonitrile or a halogenated hydrocarbon such as dichloromethane, water or an organic acid , such as acetic acid, or a mixture thereof.

Suitably an aqueous solution of hydrogen bromide, for example 48 wt. solution in water. Alternatively, the source of hydrogen bromide is a solution of hydrogen bromide in a suitable solvent, preferably a reaction solvent, for example propan-2-ol. In addition, the hydrogen bromide source can be added directly to a solution or suspension of the compound of formula I in a selected reaction solvent.

An alternative source of hydrogen bromide is a salt of hydrobromic acid with a base, for example ammonium bromide or a salt of hydrobromic acid with an amine, for example ethylamine or diethylamine.

The reaction is usually carried out at ambient or elevated temperature, for example at the reflux temperature of the solvent, although any convenient temperature at which the desired product is obtained can be used.

Solvates, such as hydrates, of the Hydrobromide are prepared by conventional methods.

Isolation of the desired compound usually involves crystallization from a suitable solvent, preferably a reaction solvent, usually by cooling to a temperature in the range of from 0 to 60 ° C, for example to 20 to 25 ° C, or from 40 to 50 ° C. For example, the hydrobromide can be crystallized from an alcohol such as propan-2-ol or a ketone such as acetone.

In one preferred embodiment, the isolation comprises an initial cooling to a first temperature, such as a temperature in the range of 40 to 50 ° C to allow crystallization to be initiated, and a subsequent cooling to a second temperature, preferably a temperature in the range of 0 to 25 ° C.

Crystallization can also be initiated by seeding with crystals of the Hydrobromide or solvate thereof, but this is not necessary.

Solvates are prepared using conventional suitable methods.

The compound of formula I is prepared by known methods, such as those described in EP 0 306 228 and WO94 / 05659. These documents are cited as a substitute for transferring their content to this text.

Matching T _sat tup / as commonly determined by differential scanning calorimetry, is as well known in the art, such as mentioned in Pharmaceutical Thermal Analysis, and Applications .Techniques, Ford and Timmins, 1989 as the temperature corresponding to the intersection of the pre-transition baseline with the extrapolated the leading edge of the transition.

The concept of good flow properties used in relation to certain compounds can be conveniently characterized by having the Hausner ratio of 1.5, most preferably 1.25.

The Hausner ratio is a term accepted in the art.

Prophylaxis of conditions associated with diabetes mellitus refers to the treatment of conditions such as insulin resistance, impaired glucose tolerance, hyperinsulinemia, and pregnancy diabetes.

Diabetes mellitus preferably means Type II diabetes mellitus.

Conditions associated with diabetes include hyperglycemia and insulin resistance and obesity. Other conditions associated with diabetes are hypertension, cardiovascular diseases, in particular atherosclerosis, certain eating disorders, particularly eating disorders and eating disorders of subjects suffering from eating disorders such as anorexia nervosis, and eating disorders such as obesity or anorexia bulimia. The conditions associated with diabetes are furthermore polycystic ovarian syndrome and steroid-induced insulin resistance.

Complications of conditions associated with diabetes mellitus include renal disease, particularly kidney disease associated with the development of type II diabetes, such as diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, and end stage renal disease.

As mentioned above, the compound of the invention has useful therapeutic properties. Accordingly, the present invention provides a Hydrobromide or solvate thereof for use as an active therapeutic agent.

More particularly, the present invention provides a Hydrobromide or solvate thereof for use in the treatment and / or prophylaxis of diabetes mellitus, conditions associated therewith and some complications thereof.

The hydrobromide or solvate thereof may be administered as such or preferably in the form of a pharmaceutical composition which also comprises a pharmaceutically acceptable carrier. Suitable methods of formulating the Hydrobromide or solvate thereof are. in general, the methods described for the compound of formula I in the above publications.

The present invention also provides a pharmaceutical composition comprising a hydrobromide or solvate thereof and a pharmaceutically acceptable carrier.

The hydrobromide or solvate thereof is normally administered in unit dosage forms.

The active compound may be administered by any suitable route, but usually orally or parenterally. In such use, the compound is normally used in the form of a pharmaceutical composition which also comprises a pharmaceutical carrier, diluent and / or excipient. However, the particular form of the composition will naturally depend on the mode of administration.

The compositions are prepared by mixing and are suitably adapted for oral, parenteral or topical administration. They may take the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, powder for reconstitution, injectable and infusible solutions or suspensions, suppositories or transdermal systems. Preferred compositions are for oral administration, especially shaped oral compositions, since they are more convenient for general use.

Tablets and capsules for oral administration usually contain a unit dose and further conventional excipients such as binders, fillers, diluents, tabletting ingredients, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents. The tablets may be coated using well known methods.

Suitable fillers include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants are, for example, starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Magnesium stearate may be mentioned as a suitable lubricant. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

Solid oral compositions may be prepared using conventional methods of blending, filling, tabletting and the like. In order to distribute the active agent in these compositions using large amounts of fillers, it is possible to employ the grinding technique, which is of course conventional in the art.

Oral liquid preparations may take the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs. They may also be in the form of a dry product to be reconstituted prior to administration using water or other suitable vehicle. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, which may include gelatin, gelatin, gelatin, edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerol, propylene glycol or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, flavoring or coloring agents.

For parenteral administration, liquid unit dosage forms are prepared comprising a compound of the invention and a sterile vehicle. The compound is suspended or dissolved depending on the vehicle and concentration. Parenteral solutions are normally prepared by dissolving the active compound in a vehicle, sterilizing the solution by filtration, and filling into suitable vials or ampoules that are sealed. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents are also dissolved in the vehicle. To enhance stability, the composition can be frozen after filling into vials and water removed under reduced pressure.

Parenteral suspensions are prepared in substantially the same manner except that the active compound is suspended in the vehicle instead of being dissolved and sterilized by treatment with ethylene oxide prior to suspension in the sterile vehicle. Surfactants or wetting agents are preferably used to facilitate the homogeneous distribution of the active compound in the composition.

As is common practice, the compositions will usually be accompanied by written or printed instructions for use in the intended treatment.

Pharmaceutically suitable means compounds, compositions and additives for both human and veterinary use. For example, the term pharmaceutically acceptable salts also includes veterinarily acceptable salts.

Another object of the invention is to provide a method of treating and / or prophylaxis of diabetes mellitus, conditions associated therewith, and certain complications thereof, for a human or other mammal which comprises administering to a human or other mammal in need thereof effective, nontoxic. an amount of the Hydrobromide or solvate thereof.

The active ingredient may conveniently be administered in the form of a pharmaceutical composition as defined above and constitutes a particular aspect of the invention.

In a further aspect, the invention provides the use of Hydrobromide or a solvate thereof for the manufacture of a medicament for the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.

In the treatment and / or prophylaxis of diabetes mellitus, conditions associated therewith and some of its complications, the Hydroiodide or solvate thereof is possible to administer in amounts that provide the compound of formula I at appropriate dosages as described in EP 0 306 228, WO94 / 05659 or WO98 / 55,122th

No harmful toxicological effects of the compounds of the invention were found in the above-described procedures.

The invention is illustrated by the following examples. These examples are illustrative only and do not limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

5- [4- [2- (N-Methyl-N- (2-pyridyl) amino) ethoxy] enyl] thiazolidin-2,4-dione hydrobromide

A mixture of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione (1.0 g) and propan-2-ol (50 mL) The mixture was stirred and heated to reflux for 10 minutes, then a clear solution was obtained. Hydrobromic acid (48 wt% solution in water, 0.31 mL) was added dropwise to the reaction mixture. The reaction mixture was stirred at reflux for 10 minutes, allowed to cool to 21 ° C. The product was filtered off and washed with propan-2-ol. There was thus obtained 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) -ethoxy] benzyl] thiazolidin-2,4-dione hydrobromide (0.41 g) as a crystalline white solid.

Example 2

5- [4- [2- (N-Methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione hydrobromide

A mixture of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione (3.0 g) and acetone (100 mL) was stirred for 15 minutes and heating to reflux when a clear solution is observed. To this solution was added hydrobromic acid (48 wt% solution in water, 0.95 mL). The reaction mixture was stirred at reflux for 15 minutes, then cooled to 21 ° C and allowed to stand for 120 hours. The mother liquor was decanted and the crystalline product was washed with acetone (10 mL) and dried under vacuum for hours. There was thus obtained 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione hydrobromide (3.7 g). ¹ H NMR (DMSO-d ₆ ): consistent with 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide containing acetone (0.5 % by weight).

Example 3

5- [4- [2- (N-Methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione hydrobromide

A mixture of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione (15.0 g) and acetone (230 mL) The mixture was stirred and heated to reflux when a clear solution was observed. To this solution was added hydrobromic acid (48 wt% solution in water, 4.75 mL). The reaction mixture was cooled to 45 ° C, stirred for 1 hour and then cooled to 50 ° C

21 ° C. The solid was filtered off and washed with acetone (100 mL). There was thus obtained 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione hydrobromide (17.7 g) as a crystalline white solid. .

Characteristic data for Hydrobromide (1) determined for the product obtained according to Example 3

Solubility of Hydrobromide

Solubility. The substances are determined by adding water to about 100 mg of the drug in aliquots of 1 to 1000 ml until the powder is dissolved. Visually determined solubility was confirmed by HPLC analysis of saturated solution.

Solubility: 6 mg / ml

Stability of hydrobromide in solid state

The solid state of the drug is determined by storing about 1.0 g of the substance in a glass container a) at 40 ° C / 75% RH, open exposure for 1 month and b) at 50 ° C, closed, for 1 month. In both cases, the substance is analyzed by HPLC for final content and degradation products.

a) 40 ° C / 75% RH: no significant degradation observed (HPLC analysis 98% initial)

b) 50 ° C: no significant degradation observed (HPLC analysis 98% starting)

Flow properties of Hydrobromide

The ratio between bulk density and tapped density (Hausner ratio) of the hydrobromide is determined using standard procedures (Pharmaceutics - The Science of Dosage Form Design, ed. M. Aulton, 1988, published by Churchill Livingstone).

Hausner ratio: 1.3

Tnastup Hydrobromid

Drug entry is determined by differential scanning calorimetry using a Perkin-Elmer DSC7.

Tp ^: 182.5 ° C

Melting point of hydrobromide

The melting point of the drug is determined by visual microscopy at high temperatures.

Melting point: 181 ° C (2) determined for the product obtained according to Example 2

The infrared absorption spectrum of the product dispersion in mineral oil was obtained using a Nicolet 710 FT-IR spectrometer at a resolution of 2 cm ^-1 (Fig. 1). Data were digitized at 1 cm ¹ intervals. The bands were observed at 2923, 2854, 2749, 1745, 1698, 1643, 1610, 1544, 1515, 1459, 1419, 1378, 1327, 1313, 128.7, 1256, 1240, 1228, 1203, 1185, 1151, 1071, 1054, 1032, 1014, 985, 906, 803, 771, 738, 712, 524 cm ^-1 .

The infrared spectrum of the solid product was recorded using universal ATR accessories. The bands were observed at 2929, 2859, 2749, 1745, 1694, 1641, 1608, 1543, 1514, 1445, 1419, 1382, 1358, 1326, 1311, 1287, 1255, 1240, 1202, 1184, 1148, 1070, 1053, 1031, 1014, 985, 906, 862, 844, 802, 768, 737, 710, 657 cm &^lt; -1 ^>.

The Raman spectrum of the product (Fig. 2) was recorded on a sample in a NMR tube using a Nicolet 960 ESP FT-Raman spectrometer at 4 cm ^-1 with excitation from a Nd: V04 (1064 nm) laser with an output power of 400 mW. The bands were observed at 3067, 2997, 2926, 2884, 2860, 1747, 1611, 1588, 1545, 1445, 1382, 1360, 1315, 1287, 1240, 1213, 1185, 1070,

1016, 986, 917, 826, 769, 740, 712, 659, 636, 620, 605, 506, 470, 405, 332, 303, 134, 99 cm ^-1 .

The X-ray powder diffractogram of the product (Fig. 3) was recorded using the following conditions: tubular anode: Cu, generator voltage: 40 kV, generator current: 40 mA, starting angle: 2.0 ° 2theta, final angle: 35.0 ° 2theta , step size: 0.02 ° 2theta, time / step: 2.5 s. The characteristic XRPD angles and relative intensity values are shown in Table 1.

Table 1

angle intensity 2theta (°) (%) 10.0 2.9 11.7 2.7 12.4 0.8 13.2 8.9 13.4 9.6 1.3,8 1.1 14.4 1.8 14.8 5.6 15.9 7.4 16.3 23.5 17.1 17.2 17.6 15.5 18.1 21.1 19.4 15.1 20.3 6.8 20.7 2.4 21.3 7.3 22.1 36.3 22.5 20.8 22.8 3 23.4 100 23.7 18 24.0 19.7 24.5 18.1 24.9 25.2 25.7 10.6 26.3 12

26.8 11.8 27.0 15.8 27.3 6.6 27.8 15.4 28.2 5 29.2 12.4 29.4 6.8 29.9 5.9 30.4 11.5 30.7 21.9 31.1 2.9 31.8 7.2 32.2 8.3 32.3 8.8 32.5 11.9 33.0 7.3 33.9 7 34.3 9 34.7 5.5

Claims (10)

PATENT CLAIMS A compound which is 5- [4- [2- (N-methyl-N (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or solvate thereof. A compound according to claim 1 having two or more of the following features: (i) the infrared spectrum substantially shown in FIG. 1? (ii) The Raman spectrum substantially shown in FIG. 2; (iii) an X-ray powder diffraction pattern substantially as set forth in Table 1 or shown in FIG. 3; (iv) a solid-state ¹³ C NMR spectrum substantially depicted in FIG. 4; and (v) a melting temperature in the range of from 175 to 185 ° C, in particular from 180 to 185 ° C, for example a melting point of 181 ° C. A compound according to claim 1 or 2 in purified form. A compound according to any one of claims 1 to 3 in solid dosage form. A compound according to any one of claims 1 to 3 in a pharmaceutically acceptable form that can be milled. A compound according to any one of claims 1 to 3 in a pharmaceutically acceptable form having good flow properties. A process for the production of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione hydrobromide or solvate thereof, characterized in that 5- [4 [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione or a salt thereof is reacted with a source of hydrogen bromide, whereupon a Hydrobromide solvate is prepared if necessary; and the hydrobromide or solvate thereof is isolated. A pharmaceutical composition comprising 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or a solvate thereof and a pharmaceutically acceptable carrier . A compound which is 5- [4- [2- (N-methyl-N (2-pyridyl) amino) ethoxy] benzyl] thiazolidine-2,4-dione hydrobromide or solvate thereof, for use as a medicament. Use of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidin-2,4-dione hydrobromide or a solvate thereof for the manufacture of a medicament for the treatment and / or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and certain complications thereof.